A reliable, highly reproducible model of bladder cancer in Fischer rats using N-(4-(5-nitro-2-furyl)-2-thiazolyl) formamide (FANFT) has been developed. The natural history of experimental bladder cancer, patterns of invasion, and dose response were determined, and also the reversibility or irreversibility of early lesions. Of numerous morphologic parameters examined, visualization with scanning electron microscopy (SEM) of pleomorphic microvilli on the luminal surface of bladder epithelial cells most closely correlated with irreversibility of early stages of carcinogenesis although the lesions were not always progressive to invasive carcinoma. Comparable changes were seen on exfoliated bladder epithelial cells in urine samples from rats with irreversible non-invasive lesions after ten weeks of FANFT, preceding recognizable light microscopic evidence of cancer in cytologic preparations by 50 weeks. Short, uniform microvilli were observed in acute regenerative cystitis produced by surgery, but pleomorphic microvilli were observed in the hyperplasia induced by cyclophosphamide injections. The methodology for examining urinary cytology by SEM from human patients has been developed, and we propose to determine the diagnostic and prognostic significance of pleomorphic microvilli in human tissue samples and cytologic material. The presence of initiation and promotion in bladder carcinogenesis was investigated using 6 weeks of 0.2% FANFT for initiation followed by a promoting agent. Sodium saccharin and DL-tryptophan significantly increased the incidence of bladder cancer in this model, but neither induced bladder lesions when fed without first feeding with FANFT in this experiment. FANFT-induced tumors in Fischer rats have been established in tissue culture and by serial transplantation. We propose to expand these studies, establishing additional tumor lines and to investigate various ultrastructural, biochemical, and immunological aspects of bladder tumors.